Alkyl and aralkyl ethers of 4a-methyl-6-hydroxy-1, 2, 3, 4, 4a, 9, 10, 10a-octahydro-1-phenanthrones



United States Patent" 6 2,764,616 V ALKYI; ETHERS F eta-METHYL- 6-' HYDROXY 1,2,3,4,4a,9,10,10a OCTAHYDRO-l- PHENANTHRONES Willard M. Ho'ehn, Wilmette, and Roy H. Bible, Jr'., Chicage, 11]., assignors, by mesne assignments, to G. D.

Sea'rl'e &' C0.', Sko"kie, 11]., a corporation of Delaware N0 Drawing'.- Application'April 29, 1952 Serial No. 285,054 Claims. (Cl; 2'60--5'90) The presentinvention relates to a new group of polycyclic ketones and' more particularly to the ethers of 4a'-m'ethyl-6 -hydroxy-1',2,3,4,4-a,9,10,IOa-octahydro-l-phenari'th'ro'nes. These compounds can be represented by the structural formula wherein R is either a lower alkyl or an aralkyl radical. Among the radicals which R can represent are methyl, ethyl, straight and branched chain propyl, butyl, amyl, and hexyl, as well as benzyl and phenethyl.

These ethers are conveniently prepared by the following procedure. An O-alkyl or O-aralkyl podocarpinol is dehydrated by a convention procedure, such as that employed by Campbell and Todd, J. Amer. Chem. Soc., 64, 933 (1942).

The mixture of the dehydration products is distilled but no further purification is attempted at that stage. The resulting oil is then dissolved in an inert organic solvent which is not attacked by ozone and treated with a mixture of ozone and air under cooling to control the reaction. The resulting ozonide is then decomposed to form the desired ketone; this decomposition is suitably accomplished by heating with water. After removal of acidic products with alkali the ketonie fraction is isolated conveniently from the reaction mixture by use of a Girard reagent such as N-hydrazidoacetopyridinium chloride, known as Girards reagent P,- which forms a derivative of the type OR C l The free ketone is regained by a'cid'ic hydrolysis. Furt-h'er purification can be achieved by chromatography.

The claimed ethers are valuable hormonal agents especially because of their estro'genic activity. Further, these ethers are valuable as intermediates in' organic synthesis. Thus dealkylation of the ether yields the free phenol, which boils at about I42-l48 C. at 0.1' mm. pressure. The methylene group at carbon-9 can be converted to a 9 o'xo group and 7-substitutiori can be achieved by introdueing a nitro group.- Important intermediates in the synthesis of steroiddike' compounds, which can be prev temperature and is thenrefiuxedfor minutes with- 2,764,616 Pa tented sept. 25, 1956 pared from these l-phenanthrones, are the 2-benzal-4amethyl-6-alkoxy-1-phenanthrones, which can be reduced to the 2-benzal-4a-methyl-6-alkoxy-l-phenanthrols.

Our invention will appeai more fully in conjunction with the following examples. It should be understood, however, that these are given by way of illustration only and that the invention is not who construed as limited thereby in spirit or in scope. It will be apparent to those skilled in the art that many modifications in materials and i methods m'ay" be made" without departing from the invention. givenulncorrected in-degrees centigrade C.), pressures in millimeters (mm.) ofmercury, and-quantities of materials in parts by Weight;

EXAMPLE 1 4a-methyl-6-methoxy-1,2',3,4;4a,9,10,10a-0ctahydr0-1- phenanthrone of chloroform, while the solution is maintained at 60 After the theoretical-amount-of ozone is passed into-the mixture, the solution is flushed for a short time with oxygen. Themixtureis allowed to come to room 200-partsof water. The organic layer is separated and the aqueous layer isextracted several times with ether. The'comb'ined organic layerand ether extracts are washed first with" 10% sodium hydroxide solution and then with wateruntilthe washings are no longer basic. The or-' ganic solution is dried over anhydrous calcium sulfate. After removal of the drying agent, the solvents are evaporatedi The'r'esidue isrefluxed for several hours With a mixture of 15 parts of Girards reagentT and 120 parts of a 10% solution of acetic acid in'methanol. The reaction mixture is cooledand"then pouredinto a mixture of'ic'e' and sufficient 10% sodium hydroxide solution to neutralize of the acetic acid: This mixture is ext'racted' 4 times with ether. The aqueous layer is shaken with 46 parts of concentrated sulfuric acid, a layer of ether is added and the mixture'is allowed to stand for 30 minut'es. The mixture is shaken' at the end of this time and-the ether layer is separated. The aqueous layer is extracted 4 times'wi'th ether. The ether solutions are combined and washed first with 10% sodium hydroxide solution'and then With water until the washings are neutrali The washed ether solutionis dried over anhydrous calcium sulfate, filtered, and stripped of solvent. The viscous yellow oil' which is obtained as the residue is distilled; using a short path distillation apparatus. The light yellow oil which dis-tills between 156 C. (0.25' mm.) and 200 C. (0.5 mm.) ischromatographed on a column containing 75 parts of alumina. The material is applied to the column in a mixture of 30% (by volume) of benzene and 70% (by volume) of low boiling petroleum ether. The chromatograplr is developed with petroleum ether boiling between 30 and 40 C. and a mixture of 30% (by volume) of benzene and 70% of petroleum ether boiling at 3040 C. The first material which is eluted with a benzene petroleum ether solution is distilled using a short path apparatus to give the pure 4a-methyl- 6-methoxy-l,2,3,4,4a,9,10110aoctahydrol-phenanfrhrone boiling ata-bout l-34--1-39- C. and 0.09 mm; pressure. An ethanol solution of this ketoneis treated with a solution of the hydrogen sulfate of 2,4-dinitrophenylhydrazine and the resulting mixture is allowed to stand at room temperature; Recrystallized from a mixture of ethanol and ethyl acetate the yellow 2,4-dinitrophenylhydrazone melts at about -1'00 C. The free ketone has an ultraviolet absorption maximum at about 280' m with an In each of theseexamples temperatures are' extinction coeflicient of 2400. It has the structural formula OCH;

CH3 l EXAMPLE 2 4a-methyl-6-eth0xy-1,2,3,4,4a,9,10,10a-octrzhydro-I- phenanth rone A solution of 9.5 parts of dehydrated O-ethylpodocarpinol boiling at about E l-140 C. and 0.1 mm. pressure in a mixture of 32 parts of carbon tetrachloride and 30 parts of chloroform is treated with a stream of ozone and oxygen at 50 C. After treatment with a theoretical amount of ozone the solution is flushed with oxygen, permitted to come to room temperature, diluted with .100 parts of water and heated at reflux temperature for 30 minutes. The organic layer is separated and the aqueous layer is extracted exhaustively with ether. The combined organic solutions are washed with 10% potassium hydroxide solution and then with water to neutrality. The organic solution is then dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is refluxed for 5 hours with a mixture of 8 parts of Girards reagent P and 60 parts of a 10% solution of acetic acid in methanol, after which the reaction mixture is cooled and poured into ice and a suflicient amount of 10% sodium hydroxide solution to neutralize 90% of the acetic acid. The resulting mixture is extracted with ether and then shaken with 23 parts of concentrated sulfuric acid. A layer of ether is added and, after standing for minutes, the mixture is shaken and the ether layer is separated. The aqueous layer is extracted with ether and the combined ether solutions are washed with 10% potassium hydroxide and then with Water to neutrality, dried over magnesium sulfate, filtered and evaporated. A viscous yellow oil is obtained which is chromatographed as in the preceding example. Upon distillation using a short path apparatus the 4a-methyl-6-ethoxy- 1,2,3,4,4a,9,10,10a-octahydro-l-phenanthrone is obtained as a clear oil distilling at about l-140 C. at 0.09 0.1 mm. pressure. This ketone has an ultraviolet absorption maximum at about 281. m with an extinction coefficient of 2500. It has the structural formula OCgHa C 3 l l 0 EXAMPLE 3 A solution of 10 parts of dehydrated O-benzylpodocarpinol in a mixture of parts of carbon tetrachloride and 50 parts of chloroform is treated with a stream of ozone and oxygen at C. and, after addition of the theoretical amount of ozone, the solution is flushed with oxygen. The reaction mixture is then diluted with 150 parts of water and heated at reflux temperature for 30 minutes after which the organic layer is separated and the aqueous layer is extracted with ether. The organic layers are combined and washed first with 10% sodium hydroxide solution and then with water to neutrality. After drying over magnesium sulfate and removal of the drying agent the solvents are evaporated and the residue is refluxed for 5 hours with a mixture of 10.5 parts of Girards reagent P and 85 parts of a 10% solution of acetic acid in methanol. After cooling the reaction mixture is treated with ice and a sufficient amount of 10% aqueous potassium hydroxide to neutralize most of the acetic acid. It is then extracted with ether and the aqueous layer is shaken with 32 parts of concentrated sulfuric acid. After standing under ether for 30 minutes the mixture is extracted with ether and the combined extracts are washed with 10% aqueous sodium hydroxide and then with water to neutrality. The extracts are dried over magnesium sulfate, filtered and the solvent is distilled. The resulting viscous oil is subjected to chromatography as in Example 1. The 4a-methyl-6-benzyloxy- 1,2,3,4,4a,9,10,lOa-octahydro-l-phenanthrone is obtained as a clear, slightly yellow, viscous high boiling oil which solidifies on standing to an amorphous solid which has the structural formula shown.

We claim:

1. The ethers of 4a-rnethyl-6-hydroxy-l,2,3,4,4a,9,l0,- l0a-octahydro-l-phenanthrone of the structural formula OR CH alkoxy)-1,2,3,4,4a,9,10,-

References Cited in the file of this patent UNITED STATES PATENTS Schwenk et al July 25, 1950 FOREIGN PATENTS France Dec. 6, 1950 OTHER REFERENCES Long: Chem. Reviews (1940), vol. 27, pp. 477 and Feiser: Organic Chemistry (1944), pp. 67 and 68; Heath & Co., Publishers, Boston.

McElvain: Characterization of Organic Compounds (1947), p. 85; MacMullen & Co., Publishers, New York. Schmidt: Organic Chemistry, 6th edition (1950),

p. 533; Gurney and Jackson, London, Publisher. 

1. THE ETHERS OF 4A-METHYL-6-HYDROXY-1,2,4,4A,9,10,10A-OCTAHYDRO-1-PHENANTHRONE OF THE STRUCTURAL FORMULA 